Project Summary Many metabolic and hormonal factors have been identified in the peripheral olfactory system. Because food odor is a major determinant for food choice and acceptance, these factors are thought to modulate olfactory perception and the hedonic value of odors to control food intake. One such incretin peptide, glucagon-like peptide (GLP-1), has several beneficial pleiotropic effects both in peripheral tissues and in the central nervous system, including the suppression of food intake, an increase in cardiac function, and neuroprotection. Anatomical studies conducted by us and others have revealed the expression of GLP-1 peptide and its unique receptor at the level of the olfactory bulb. My preliminary data have shown that direct application of GLP-1 on olfactory bulb slices results in an important increase of the action potential frequency in mitral cells. Because little is known about the mechanisms underlining the modulation of olfaction with the nutritional state and the fact that GLP-1 analogues are being used as a therapeutic means to control type II diabetes, the GOAL of this project will be to elucidate the functional role of GLP-1 in the olfactory bulb. Given that mitral cells constitute the first relay of olfactory information between olfactory sensory neurons and the central areas responsible for olfactory processing, I HYPOTHESIZE that GLP-1 signaling pathway in the olfactory bulb can be an important regulator of olfactory input. The experiments proposed in this application employ a multidisciplinary approach divided into three different SPECIFIC AIMS, which will explore the physiological role of the GLP-1 signaling pathway in olfaction - 1) To determine the intrinsic electrophysiological properties of genetically-identified GLP-1 neurons in an olfactory bulb slice preparation using a fluorescent reporter under the control of the preproglucagon (PPG; precursor of GLP-1) promoter and to map the associated synaptic connections by immunocytochemistry. 2) To chemically (direct GLP-1 application) and optogenetically (engineered channelrohodopsin-2 mice in PPG-CRE recombinant background) stimulate PPG-neurons to define the excitability of mitral cells by slice electrophysiology in the whole-cell configuration. 3) To deliver GLP-1 analogs and antagonists in vivo to measure changes in olfactory behavior (olfactometry) and food intake (whole-system physiology, metabolic chambers). PUBLIC HEALTH RELAVANCE STATEMENT: The latest statistics report that 65% of Americans are overweight, while diet-induced or type II diabetes is becoming epidemic in our population. The anticipated results of this study will not only provide a better fundamental understanding of the physiological regulation of olfactory perception in context with the metabolic status of the individual, but it may identify a potential therapeutic target to control overeating; a main cause of obesity in western countries.